Arachidonic acid serves as the biological precursor of a growing family of physiologically active eicosanoids which include cyclooxygenase derived products such as prostaglandins-E's and F's, thromboxanes, prostacyclin, and lipoxygenase-derived products such as hydroperoxy- and hydroxy-eicosatetraenoic acids (HPETE and HETE) and leukotrienes.
Recently, lipoxygenase pathway products such as leukotrienes-B.sub.4, C.sub.4, and D.sub.4, 5-HPETE; 5-HETE and 12-HETE have been implicated in inflammation and in allergic and immune responses. These lipoxygenase products have been shown to be highly potent, stereospecific inducers of polymorphonuclear leukocyte migration or chemotaxis, lysosomal enzyme release and degranulation, as well as contraction of smooth muscles such as vascular and pulmonary tissue, and induce the generation of additional inflammogens such as thromboxane A.sub.2 and prostacyclin. Lipoxygenase products also interact with vasodilator prostanoids and other mediators which leads to an enhancement or amplification of the inflammatory response.
Leukotrienes and HETES play a major role in the pathogenesis of many conditions. They have been found in synovial fluid of rheumatoid joints, in involved skin of psoriatic patients, in inflamed colonic tissue, and elevated in ischemic myocardial tissue. They are major mediators of allergic and asthmatic conditions as well.
Lipoxygenase inhibitors or leukotriene biosynthesis inhibitors will thus be useful in treating a number of diseases whose pathogenesis involves production of leukotrienes and other lipoxygenase derived products and subsequent tissue damage or inflammation due to infiltration of leukocytes, release of digestive lysosomal enzymes, changes in permeability, and contractile state of smooth muscle tissue. Conditions in which such inhibitors would be useful include allergy, asthma, arthritis, psoriasis, inflammation, inflammatory bowel diseases, pain, and cardiovascular disorder such as myocardial ischemia and infarction, stroke, and atherosclerosis.